Working Memory: From Neural Activity to the Sentient Mind.

Working memory (WM) is the ability to maintain and manipulate information in the conscious mind over a timescale of seconds. This ability is thought to be maintained through the persistent discharges of neurons in a network of brain areas centered on the prefrontal cortex, as evidenced by neurophysiological recordings in nonhuman primates, though both the localization and the neural basis of WM has been a matter of debate in recent years. Neural correlates of WM are evident in species other than primates, including rodents and corvids. A specialized network of excitatory and inhibitory neurons, aided by neuromodulatory influences of dopamine, is critical for the maintenance of neuronal activity. Limitations in WM capacity and duration, as well as its enhancement during development, can be attributed to properties of neural activity and circuits. Changes in these factors can be observed through training-induced improvements and in pathological impairments. WM thus provides a prototypical cognitive function whose properties can be tied to the spiking activity of brain neurons. © 2021 American Physiological Society. Compr Physiol 11:1-41, 2021.

Emergence of Nonlinear Mixed Selectivity in Prefrontal Cortex after Training.

Neurons in the PFC are typically activated by different cognitive tasks, and also by different stimuli and abstract variables within these tasks. A single neuron's selectivity for a given stimulus dimension often changes depending on its context, a phenomenon known as nonlinear mixed selectivity (NMS). It has previously been hypothesized that NMS emerges as a result of training to perform tasks in different contexts. We tested this hypothesis directly by examining the neuronal responses of different PFC areas before and after male monkeys were trained to perform different working memory tasks involving visual stimulus locations and/or shapes. We found that training induces a modest increase in the proportion of PFC neurons with NMS exclusively for spatial working memory, but not for shape working memory tasks, with area 9/46 undergoing the most significant increase in NMS cell proportion. We also found that increased working memory task complexity, in the form of simultaneously storing location and shape combinations, does not increase the degree of NMS for stimulus shape with other task variables. Lastly, in contrast to the previous studies, we did not find evidence that NMS is predictive of task performance. Our results thus provide critical insights on the representation of stimuli and task information in neuronal populations, in working memory.SIGNIFICANCE STATEMENT How multiple types of information are represented in working memory remains a complex computational problem. It has been hypothesized that nonlinear mixed selectivity allows neurons to efficiently encode multiple stimuli in different contexts, after subjects have been trained in complex tasks. Our analysis of prefrontal recordings obtained before and after training monkeys to perform working memory tasks only partially agreed with this prediction, in that nonlinear mixed selectivity emerged for spatial but not shape information, and mostly in mid-dorsal PFC. Nonlinear mixed selectivity also displayed little modulation across either task complexity or correct performance. These results point to other mechanisms, in addition to nonlinear mixed selectivity, representing complex information about stimulus and task context in neuronal activity.

Recent Advances in the Development of Integrase Inhibitors for HIV Treatment.

PURPOSE OF THE REVIEW: The complex multistep life cycle of HIV allows it to proliferate within the host and integrate its genome in to the host chromosomal DNA. This provirus can remain dormant for an indefinite period. The process of integration, governed by integrase (IN), is highly conserved across the Retroviridae family. Hence, targeting integration is not only expected to block HIV replication but may also reveal new therapeutic strategies to treat HIV as well as other retrovirus infections. RECENT FINDINGS: HIV integrase (IN) has gained attention as the most promising therapeutic target as there are no equivalent homologues of IN that has been discovered in humans. Although current nano-formulated long-acting IN inhibitors have demonstrated the phenomenal ability to block HIV integration and replication with extraordinary half-life, they also have certain limitations. In this review, we have summarized the current literature on clinically established IN inhibitors, their mechanism of action, the advantages and disadvantages associated with their therapeutic application, and finally current HIV cure strategies using these inhibitors.

Alpha-Band Activity Reveals Spontaneous Representations of Spatial Position in Visual Working Memory.

An emerging view suggests that spatial position is an integral component of working memory (WM), such that non-spatial features are bound to locations regardless of whether space is relevant [1, 2]. For instance, past work has shown that stimulus position is spontaneously remembered when non-spatial features are stored. Item recognition is enhanced when memoranda appear at the same location where they were encoded [3-5], and accessing non-spatial information elicits shifts of spatial attention to the original position of the stimulus [6, 7]. However, these findings do not establish that a persistent, active representation of stimulus position is maintained in WM because similar effects have also been documented following storage in long-term memory [8, 9]. Here we show that the spatial position of the memorandum is actively coded by persistent neural activity during a non-spatial WM task. We used a spatial encoding model in conjunction with electroencephalogram (EEG) measurements of oscillatory alpha-band (8-12 Hz) activity to track active representations of spatial position. The position of the stimulus varied trial to trial but was wholly irrelevant to the tasks. We nevertheless observed active neural representations of the original stimulus position that persisted throughout the retention interval. Further experiments established that these spatial representations are dependent on the volitional storage of non-spatial features rather than being a lingering effect of sensory energy or initial encoding demands. These findings provide strong evidence that online spatial representations are spontaneously maintained in WM-regardless of task relevance-during the storage of non-spatial features.

A simplified pathway for total knee arthroplasty improves outcomes.

Care pathways for total knee arthroplasty (TKA) demonstrate improved quality and utilization outcomes. Standardizing these processes over large systems is difficult due to the variability of practice patterns and the complexity of multistep pathways. A simplified approach to this process focusing on early activity and avoidance of continuous urinary catheters was performed to overcome these perceived barriers for implementing a system-wide care pathway. Data were collected from a total of 6,154 consecutive patients during the time period of 1 year before and 1 year after implementation of a pathway focusing on two key drivers: early activity and continuous urinary catheter avoidance. Patients included were adults admitted for elective primary TKA. A composite score was calculated based on the successful completion of the two key drivers. Outcome measures were tracked before and after implementation. Following implementation of a simplified TKA care pathway, there was a significant increase in the composite score with increases attributable to both increased early activity (p < 0.0001) and continuous urinary catheter avoidance (p < 0.0001). This improvement in composite score was associated with a significant decrease in hospital length of stay (HLOS) (p < 0.0001), costs (p < 0.0001), complications (p < 0.0001), and 30-day readmissions (p < 0.0106). A fixed-effect model analysis demonstrated early activity was associated with improvements in HLOS (p < 0.0001), complications (p = 0.0240), and 30-day readmissions (p = 0.0046). Avoidance of a continuous urinary catheter was associated with improvements in HLOS (p = 0.0001), costs (p < 0.0001), complications (p = 0.0006), and 30-day readmissions (p = 0.0008). A simplified care pathway for TKA focusing on early activity and continuous urinary catheter avoidance is associated with improved complications, costs, HLOS, and 30-day readmissions.